The Effect of Potassium Canrenoate (Mineralocorticoid Receptor Antagonist) on the Markers of Inflammation in the Treatment of COVID-19 Pneumonia and Fibrosis-A Secondary Analysis of Randomized Placebo-Controlled Clinical Trial.

In March 2020, the World Health Organization (WHO) announced a global pandemic of coronavirus disease 2019 (COVID-19) that presented mainly as an acute infection of the lower respiratory tract (pneumonia), with multiple long-term consequences, including lung fibrosis. The aim of this study was to evaluate the influence of potassium canrenoate on inflammatory markers in the treatment of COVID-19 pneumonia. A randomized clinical trial (RCT) of intravenous potassium canrenoate vs. placebo was performed between December 2020 and November 2021. This study is a secondary analysis of that RCT. In the final analysis, a total of 49 hospitalized patients were included (24 allocated to the potassium canrenoate group and 25 to the placebo group). Patients were assessed by serum testing and blood cell cytometry on day 1 and day 7 of the intervention. Age, sex, and body mass index were not significantly different between the placebo group and intervention group. Although there was a significantly higher rate of ischemic heart disease in the placebo group, rates of other preexisting comorbidities were not significantly different. There were no significant differences in the inflammatory parameters between the potassium canrenoate and placebo groups on day 1 and day 7. However, the intragroup comparisons using Wilcoxon's test showed significant differences between day 1 and day 7. The CD3% for potassium canrenoate increased significantly between day 1 and day 7 (12.85 ± 9.46; 11.55 vs. 20.50 ± 14.40; 17.80; p = 0.022), while the change in the placebo group was not significant (15.66 ± 11.39; 12.65 vs. 21.16 ± 15.37; 16.40; p = 0.181). The IL-1ß total count [%] increased over time for both potassium canrenoate (0.68 ± 0.58; 0.45 vs. 1.27 ± 0.83; 1.20; p = 0.004) and placebo (0.61 ± 0.59; 0.40 vs. 1.16 ± 0.91; 1.00; p = 0.016). The TNF-α total count (%) decreased significantly between day 1 and day 7 for potassium canrenoate (0.54 ± 0.45; 0.40 vs. 0.25 ± 0.23; 0.10; p = 0.031), but not for placebo (0.53 ± 0.47; 0.35 vs. 0.26 ± 0.31; 0.20; p = 0.056). Interleukin-6 (pg/mL) showed a significant decrease between day 1 and day 7 for potassium canrenoate (64.97 ± 72.52; 41.00 vs. 24.20 ± 69.38; 5.30; p = 0.006), but not the placebo group. This RCT has shown that the administration of potassium canrenoate to patients with COVID-19-induced pneumonia may be associated with significant changes in certain inflammatory markers (interleukin-6, CD3%, TNF-α), potentially related to pulmonary fibrosis. Although some positive trends were observed in the potassium canrenoate group, none of these observations reached statistical significance. Any possible benefits from the use of potassium canrenoate as an anti-inflammatory or antifibrotic drug in COVID-19 patients require further investigation.

Intravenous Mineralocorticoid Receptor Antagonist Use in Acutely Decompensated Heart Failure with Diuretic Resistance.

Intravenous mineralocorticoid receptor antagonists (MRAs) have been used in some centers for decades to reduce the risk of hypokalemia and boost diuresis in acutely decompensated heart failure (ADHF). We report the well-tolerated use of intravenous MRAs as a rescue procedure in 3 patients admitted for ADHF with important diuretic resistance. Undertaking trials evaluating the effect of this therapeutic strategy in ADHF could represent a promising avenue.

Clinical efficacy of potassium canreonate-canrenone in sinus rhythm restoration among patients with atrial fibrillation - a protocol of a pilot, randomized, double -blind, placebo-controlled study (CANREN-AF trial).

BACKGROUND: Atrial fibrillation (AF) is the most frequent cardiac arrhythmia which increases the risk of thromboembolic complications and impairs quality of life. An important part of a therapeutic approach for AF is sinus rhythm restoration. Antiarrhythmic agents used in pharmacological cardioversion have limited efficacy and potential risk of proarrhythmia. Simultaneously, underlying conditions of AF should be treated (e.g. electrolyte imbalance, increased blood pressure, neurohormonal disturbances, atrial volume overload). There is still the need for an effective and safe approach to increase AF cardioversion efficacy. This randomized, double-blind, placebo-controlled, superiority clinical study is performed in patients with AF in order to evaluate the clinical efficacy of intravenous canrenone in sinus rhythm restoration. METHODS: Eighty eligible patients with an episode of AF lasting less than 48 h are randomized in a 1:1 ratio to receive canrenone or placebo. Patients randomized to a treatment intervention are receiving canrenone intravenously at a dose of 200 mg within 2-3 min. Subjects assigned to a control group obtain the same volume of 0.9% saline within the same time. The primary endpoint includes return of sinus rhythm documented in the electrocardiogram within 2 h after drug or placebo administration. Other endpoints and safety outcomes analyses, due to expected lack of statistical power, are exploratory. DISCUSSION: Current evidence supports renin-angiotensin-aldosterone system (RAAS) inhibition as an upstream therapy in AF management. Excess aldosterone secretion results in proarrhythmic effects. Among the RAAS inhibitors, only canrenone is administered intravenously. Canrenone additionally increases the plasma level of potassium, lowers blood pressure and reduces preload. It has been already used in primary and secondary hyperaldosteronism in the course of chronic liver dysfunction and in heart failure. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03536806. Registered on 25 May 2018.

Cutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade.

Skin ulcers resulting from impaired wound healing are a serious complication of diabetes. Unresolved inflammation, associated with the dysregulation of both the phenotype and function of macrophages, is involved in the poor healing of diabetic wounds. Here, we report that topical pharmacological inhibition of the mineralocorticoid receptor (MR) by canrenoate or MR small interfering RNA can resolve inflammation to improve delayed skin wound healing in diabetic mouse models; importantly, wounds from normal mice are unaffected. The beneficial effect of canrenoate is associated with an increased ratio of anti-inflammatory M2 macrophages to proinflammatory M1 macrophages in diabetic wounds. Furthermore, we show that MR blockade leads to downregulation of the MR target, LCN2, which may facilitate macrophage polarization toward the M2 phenotype and improve impaired angiogenesis in diabetic wounds. Indeed, diabetic LCN2-deficient mice showed improved wound healing associated with macrophage M2 polarization and angiogenesis. In addition, recombinant LCN2 protein prevented IL-4-induced macrophage switch from M1 to M2 phenotype. In conclusion, topical MR blockade accelerates skin wound healing in diabetic mice via LCN2 reduction, M2 macrophage polarization, prevention of inflammation, and induction of angiogenesis.

Mineralocorticoid receptor antagonist pre-treatment and early post-treatment to minimize reperfusion injury after ST-elevation myocardial infarction: The MINIMIZE STEMI trial.

BACKGROUND: Mineralocorticoid receptor antagonist (MRA) therapy has been shown to prevent adverse left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients with heart failure. Whether initiating MRA therapy prior to primary percutaneous coronary intervention (PPCI) accrues additional benefit of reducing myocardial infarct size and preventing adverse LV remodeling is not known. We aimed to investigate whether MRA therapy initiated prior to reperfusion reduces myocardial infarct (MI) size and prevents adverse LV remodeling in STEMI patients. METHODS: STEMI patients presenting within 12 hours and with a proximal coronary artery occlusion with Thrombolysis In Myocardial Infarction flow grade 0 were consented and randomized to either an intravenous bolus of potassium canrenoate, followed by oral spironolactone for 3 months or matching placebo. The primary endpoint was MI size by cardiovascular magnetic resonance at 3 months. RESULTS: Sixty-seven patients completed the study. There was no significant difference in the final MI size at 3 months between the 2 groups (placebo: 17 ± 11%, MRA: 16 ± 10%, P = .574). There was also no difference in acute MI size (26 ± 16% versus 23 ± 14%, P = .425) or myocardial salvage (26 ± 12% versus 24 ± 8%, P = .456). At follow-up, there was a trend towards an improvement in LVEF (placebo: 49 ± 8%, MRA: 54 ± 11%, P = .053), and the MRA group had significantly greater percentage decrease in LVEDV (mean difference: -12.2 (95% CI -20.3 to -4.4)%, P = .003) and LVESV (mean difference: -18.2 (95% CI -30.1 to -6.3)%, P = .003). CONCLUSION: This pilot study showed no benefit of MRA therapy in reducing MI size in STEMI patients when initiated prior to reperfusion, but there was an improvement in LV remodeling at 3 months. Adequately powered studies are warranted to confirm these findings.

Importance of the time of initiation of mineralocorticoid receptor antagonists on risk of mortality in patients with heart failure.

INTRODUCTION: Several studies have definitively shown the benefit of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure (HF). However, very few prior studies examined the relationship between the timing of initiation of MRAs and prognosis. In addition, on this topic, there is no information regarding the specific population of patients suffering a first episode of decompensated congestive HF. METHODS: We studied a homogenous cohort of patients discharged alive from our hospital after a first episode of decompensated congestive HF, in order to clarify the association between time of aldosterone receptor antagonist (ARA) initiation (within the first 90 days after hospital discharge) and mortality. Our population was composed of a series of consecutive patients. All-cause mortality was compared between patients who initiated MRAs at discharge (early group) and those who initiated MRAs one month later and up to 90 days after discharge (delayed group). We used prescription time distribution matching to control for survival difference between groups. RESULTS: The early and delayed groups consisted of 365 and 320 patients, respectively. During the one-year follow-up, a significant difference in mortality was demonstrated between groups. Adjusted hazard ratios (HRs) for early versus delayed initiation were 1.72 (95% confidence interval (CI) 0.96 to 2.84) at six months, and 1.93 (95% CI 1.18 to 3.14) at one year. CONCLUSIONS: Delay of MRA initiation up to 30 to 90 days after discharge implies a significant increase in mortality compared with MRA initiation at discharge, after a first episode of decompensate congestive HF.

Potassium canrenoate treatment in paediatric patients: a population pharmacokinetic study using novel dried blood spot sampling.

OBJECTIVE: To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate (K-canrenoate) in paediatric patients. METHODS: Data were collected prospectively from 37 paediatric patients (median weight 2.9 kg, age range 2 days-0.85 years) who received intravenous K-canrenoate for management of retained fluids, for example in heart failure and chronic lung disease. Dried blood spot (DBS) samples (n=213) from these were analysed for canrenone content and the data subjected to pharmacokinetic analysis using nonlinear mixed-effects modelling. Another group of patients (n=16) who had 71 matching plasma and DBS samples was analysed separately to compare canrenone pharmacokinetic parameters obtained using the two different matrices. RESULTS: A one-compartment model best described the DBS data. Significant covariates were weight, postmenstrual age (PMA) and gestational age. The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) in DBS were CL/F (l/h) = 12.86 ×  (WT/70.0) × e [0.066 ×  (PMA - 40]) and V/F (l) = 603.30 ×  (WT/70) × (GA/40) where weight is in kilograms. The corresponding values of CL/F and V/F in a patient with a median weight of 2.9 kg are 1.11 l/h and 20.48 l, respectively. Estimated half-life of canrenone based on DBS concentrations was similar to that based on matched plasma concentrations (19.99 and 19.37 h, respectively, in 70 kg patient). CONCLUSION: The range of estimated CL/F in DBS for the study population was 0.12-9.62 l/h; hence, bodyweight-based dosage adjustment of K-canrenoate appears necessary. However, a dosing scheme that takes into consideration both weight and age (PMA/gestational age) of paediatric patients seems more appropriate.

Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Little is known about the pharmacokinetics of potassium canrenoate/canrenone in paediatric patients WHAT THIS STUDY ADDS: A population pharmacokinetic model has been developed to evaluate the pharmacokinetics of canrenone in paediatric patients who received potassium canrenoate as part of their therapy in the intensive care unit. AIMS To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate to paediatric patients. METHODS: Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16-28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids, e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analyzed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. RESULTS: A one compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (l h(-1) ) = 11.4 × (WT/70.0)(0.75) and V/F (l) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 l h(-1) and 21.4 l, respectively, resulting in an elimination half-life of 11.2 h. CONCLUSIONS: The range of estimated CL/F in the study population was 0.67-7.38 l h(-1) . The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients.

Amiloride reduces portal hypertension in rat liver cirrhosis.

OBJECTIVE: This study aimed to investigate the effect of amiloride on portal hypertension. Amiloride is known to inhibit Na(+)/H(+) exchangers on activated hepatic stellate cells. METHODS: Liver cirrhosis in rats was induced by bile duct ligation (BDL) or thioacetamide (TAA) administration. The effects of zymosan for Kupffer cell (KC) activation or a thromboxane (TX) analogue (U46619) were tested in isolated perfused livers of cirrhotic rats and in vivo. Downstream mechanisms were investigated using Rho kinase inhibitor (Y-27632) or amiloride. Acute and chronic effects of amiloride and canrenoate on portal pressure were compared in perfused livers and in vivo. TXB(2) efflux was measured by ELISA. The phosphorylation state of moesin (p-moesin) as an indicator of Rho kinase activity and expression of the thromboxane synthase were assessed by western blot analyses. The activity of hepatic stellate cells was analysed by western blot and staining for alpha-smooth muscle actin (alpha-SMA). RESULTS: In BDL rats, KC activation via zymosan increased portal pressure. This was attenuated by the Rho kinase inhibitor Y-27632. Increased thromboxane efflux following zymosan infusion remained unaltered by Y-27632. The infusion of amiloride attenuated zymosan- and U46619-induced increases in portal perfusion pressure. In vivo, direct administration of amiloride, but not of canrenoate, lowered portal pressure. In TAA and BDL rats, treatment with amiloride for 3 days reduced basal portal pressure and KC-induced increases in portal pressure whereas canrenoate had no effect. In livers of amiloride-treated animals, the phosphorylation state of moesin and the number of alpha-SMA positive cells were reduced. CONCLUSIONS: Amiloride lowers portal pressure in rat liver cirrhosis by inhibition of intrahepatic vasocontraction. Therefore, patients with cirrhosis and portal hypertension may benefit from amiloride therapy.

Cardioprotective effects of mineralocorticoid receptor antagonists at reperfusion.

AIMS: Pre-treatment with mineralocorticoid receptor (MR) antagonists is reported to reduce myocardial infarct size from ischaemia/reperfusion. Here, we tested whether the MR antagonists potassium canrenoate and eplerenone could protect in the more clinically relevant schedule of administration at the end of ischaemia. METHODS AND RESULTS: In all models, hearts were subjected to 30 min regional ischaemia followed by 120 min (rabbits 4 h) reperfusion. A bolus of canrenoate 5 min prior to reperfusion in open-chest mice decreased infarct size in a dose-dependent manner. Maximum protection was seen at 1 mg/kg where infarction was 18% of that in the control (P < 0.001). Ecto-5'-nucleotidase (CD73) as well as adenosine A(2b) receptor knock-out mice could no longer be protected, suggesting a role for adenosine and the A(2b) receptor in the mechanism. A 1 mg/kg bolus of canrenoate prior reperfusion also reduced infarct size in open-chest rabbits. To explore the underlying mechanisms, we studied isolated rat hearts. Eplerenone (10 microM) at the end of ischaemia was similarly protective in the rat heart and the protection was abolished by co-treatment with inhibitors of the adenosine receptor, protein kinase C, PI3-kinase, and ERK. In addition, eplerenone or canrenoate treatment increased phosphorylation of the pro-survival kinases Akt and ERK1/2 at reperfusion in the rat hearts. CONCLUSION: Taken together, MR antagonists when given at the end of ischaemia are highly effective and potent cardioprotective drugs with a signalling similar to that of ischaemic pre-conditioning and, hence, could be a very promising candidate for the treatment of acute myocardial infarction in man.

Time-course reduction of renal function in rats on high sodium intake: acute reversal by potassium canrenoate.

1. Time course of renal alterations associated with long-term (since weaning) administration of a high sodium (HS, 8% NaCl) diet was assessed in Sprague-Dawley rats. Reversal by acute administration of the mineralocorticoid receptor antagonist, potassium canrenoate (40 mg/kg, i.p.) or the type 1 angiotensin II receptor antagonist, losartan (10 mg/kg, i.v.), was evaluated at the age of 5 months (i.e. after 21 weeks of HS feeding). 2. High sodium intake had no detectable effect on blood pressure; however, albuminuria was always higher in the HS than control group. Glomerular filtration rate, renal plasma flow and filtration fraction decreased significantly after 12 weeks of HS diet by approximately 50, 30 and 20%, respectively. Canrenoate was effective and markedly reversed the renal hypofiltration associated with HS feeding without change in systemic blood pressure. In contrast, losartan reduced blood pressure and it was devoid of a beneficial effect on renal function. 3. The present observations indicate that hypofiltration and hypoperfusion of the kidney occurred progressively and require a long period of exposure to a high sodium intake. Albuminuria, which increased before detectable changes in renal function, may represent an early marker of renal dysfunction. The beneficial effect of acute administration of potassium canrenoate favours the participation of aldosterone, at least partially, in the sustained deterioration of renal function after 21 weeks of high sodium feeding.

Mineralocorticoid receptor antagonists.

With an increasingly aging population, the need for effective treatment of cardiovascular diseases (eg, heart failure, hypertension, and ischemic heart disease) cannot be overemphasized. The vital importance of mineralocorticoid receptor antagonists for treating cardiovascular conditions has only been appreciated in the last decade. The re-emergence of mineralocorticoid receptor antagonists has provided clinicians with an important tool towards complete blockade of the renin-angiotensin-aldosterone axis.

Effect of potassium canrenoate, an anti-aldosterone agent, on incidence of ascites and variceal progression in cirrhosis.

BACKGROUND & AIMS: Because aldosterone-dependent sodium and water retention contribute to portal hypertension, the safety and effect of an antialdosteronic drug (Kcanrenoate) have been evaluated on the occurrence of de novo appearance of ascites and the development of esophageal varices or the progression of small varices. METHODS: Inclusion criteria were as follows: Child-Pugh A viral pre-ascitic cirrhosis, with either F1 esophageal varices or no varices, but endoscopic and/or ultrasound evidence of portal hypertension. Thirteen Italian Liver Units prospectively enrolled 120 patients randomized to receive double-blind either Kcanrenoate (100 mg/day; 66 patients) or placebo (54 patients). Endoscopy and sonography were performed at entry and at 52 weeks unless the patient developed ascites earlier, whereas laboratory examinations were performed at entry and every 3 months thereafter. An intention-to-treat analysis was performed, with each end point assessed by the Fisher exact test; the cumulative risk for the appearance of any end point was analyzed by the adjusted log-rank test (Tarone-Ware), with censoring for drop-outs. RESULTS: The progression of variceal status or appearance of ascites, analyzed independently, was not significantly more frequent on placebo (24.1% and 9.2%, respectively) than on Kcanrenoate (12.1% and 1.5%, respectively), whereas the cumulative occurrence of end points was decreased on Kcanrenoate (17.6% vs 38.3% with placebo; P < .05, Tarone-Ware test). The incidence of adverse events was negligible and did not differ between groups. CONCLUSIONS: This preliminary study shows that 100 mg/day of Kcanrenoate is well tolerated and does not reduce the individual incidence of ascites and/or the appearance or progression of esophageal varices in preascitc cirrhosis, but may decrease their 1-year cumulative occurrence.

Idiopathic primary hyperaldosteronism: normalization of plasma aldosterone after one month withdrawal of long-term therapy with aldosterone-receptor antagonist potassium canrenoate.

We have re-evaluated 15 patients with idiopathic primary aldosteronism one month after withdrawal of therapy with aldosterone-receptor antagonist potassium canrenoate. Therapy had lasted for 3 to 24 yr. Median blood pressure (BP) in the sitting position at the time of diagnosis was 160/100 (ranges 150-200/95-110 mmHg); while 1 month after withdrawal of therapy median BP was 145/90 (ranges 125-160/80-100 mmHg). One month after withdrawal, the ratio aldosterone (ng/dl)/plasma renin activity (ng/ml/h) in the upright position was increased only in 3 cases (median 18, range 6.1-125). We found a significant inverse correlation between the upright aldosterone/plasma renin activity (aldo/PRA) ratio, 1 month after withdrawal, and the number of years of therapy with potassium canrenoate. We conclude that long-term therapy with the aldosterone-receptor blocker, potassium canrenoate, can normalize the aldo/PRA ratio in many cases of idiopathic primary hyperaldosteronism after one-month withdrawal of the drug. These data are consistent with possible regression of idiopathic primary hyperaldosteronism after long-term therapy with potassium canrenoate, or in alternative to a persistent effect of potassium canrenoate, on aldosterone synthesis.

Cardiac, neuroadrenergic, and portal hemodynamic effects of prolonged aldosterone blockade in postviral child A cirrhosis.

OBJECTIVES: The present study was designed to determine the effects of long-term antialdosterone treatment on cardiac structural and functional alterations, portal and systemic hemodynamic as well as adrenergic dysfunction characterizing Child A cirrhotic patients with F1 esophageal varices. METHODS: Twenty-two Child A postviral preascitic cirrhotic patients were randomly allocated to 200 mg/day K-Canrenoate (13 patients, age 59.6 +/- 2.2 yr, mean + SEM) or no-drug treatment (9 patients, age 61.8 +/- 2.3) for a 6-month-period. Measurements, which included hepatic venous pressure gradient (HVPG), left ventricular wall thickness, left ventricular end-diastolic volume and diastolic function (LVWT, LVEDV, and E/A ratio, echocardiography), and muscle sympathetic nerve activity (MSNA, microneurography, peroneal nerve), were obtained at baseline and following 6 months of drug or no-drug treatment. Ten healthy age-matched subjects served as controls. RESULTS: Cirrhotic patients were characterized by increased HVPG, LVWT, and MSNA values and by a depressed E/A ratio. K-Canrenoate treatment significantly reduced HVPG (from 15.3 +/- 1.0 to 13.8 +/- 0.8 mmHg, p < 0.05), LVWT (from 21.8 +/- 0.5 to 20.7 +/- 0.6 mm, p < 0.02), and LVEDV (from 99.2 +/- 7 to 86.4 +/- 6 ml, p < 0.01), leaving E/A ratio and MSNA almost unaltered. No significant change was observed in the untreated group of cirrhotic patients followed for 6 months without intervention. CONCLUSIONS: These data provide evidence that aldosterone blockade by long-term K-Canrenoate administration improves hepatic hemodynamics by lowering HVPG and ameliorates cardiac structure and function by favoring a reduction in LVWT and LVEDV as well. They also show, however, that this therapeutic intervention neither improves left ventricular diastolic dysfunction nor exerts sympathoinhibitory effects.

Acute aldosterone antagonism improves cardiac vagal control in humans.

OBJECTIVES: We have examined the acute effects (<45 min) of aldosterone antagonism on heart rate variability and baroreflex sensitivity, markers of cardiac vagal control, in 13 healthy subjects. BACKGROUND: Evidence for the beneficial effects of aldosterone antagonists comes from studies showing increased survival rates following their addition to standard heart failure therapy. Many mechanisms have been suggested for this action, including effects upon the autonomic nervous system. METHODS: Heart rate variability and baroreflex sensitivity were examined 30 min following the administration of potassium canrenoate (intravenous) (aldosterone antagonist) or saline (control). RESULTS: Active treatment reduced resting heart rate (-6 +/- 1 beats/min [mean +/- standard error mean]) compared to control (0 +/- 1 beat/min) (p < 0.001) and increased measures of high frequency (HF) heart rate variability. Root mean square of successive RR interval differences increased by 21 +/- 5 ms versus -6 +/- 5 ms control (p < 0.001); HF power increased by 1,369 +/- 674 ms(2)with aldosterone antagonism compared to -255 +/- 431 ms(2) following saline infusion (p < 0.01). Baroreflex sensitivity (alpha-HF) was increased after active treatment (+4 +/- 2 ms/mm Hg vs. 0 +/- 1 ms/mm Hg control [p < 0.05]). No changes in plasma potassium levels were observed. CONCLUSIONS: These results provide evidence that aldosterone antagonists acutely improve cardiac vagal control, irrespective of any diuretic effects, and may in part explain their beneficial effects in treatment of heart failure.

Potassium canrenoate, an aldosterone receptor antagonist, reduces isoprenaline-induced cardiac fibrosis in the rat.

The purpose of the present study was to determine whether the administration of an antagonist of aldosterone could prevent the fibrosis induced by an acute injection of isoprenaline. Male Wistar rats were submitted to one subcutaneous injection of isoprenaline (400 mg/kg) and were simultaneously treated with potassium canrenoate in drinking water (20 mg/kg/day) started 5 days before the injection of isoprenaline. Two months later, echocardiographic and hemodynamic measurements were performed. Then, the heart was prepared for morphometric histology and quantification of fibrosis in the left ventricle. Heart and left ventricular weights were increased significantly by isoprenaline. Potassium canrenoate attenuated this increase. The administration of isoprenaline increased significantly end diastolic diameter and end systolic volume compared with control. These changes were increased further with the addition of potassium canrenoate. In contrast, the fibrosis induced by isoprenaline was reduced significantly by potassium canrenoate at the three section levels. Potassium canrenoate attenuated the fibrosis but not the enhanced dilatation of the left ventricle induced by isoprenaline.

Comparative evaluation of digoxin concentrations determined by three assay systems: TDx, IMx and OPUS.

Digoxin concentrations measured by three automated immunoassay systems, i.e. OPUS, TDx and IMx assays, were compared in order to evaluate precision and accuracy performance, and data compatibility. Coefficients of variation for all methods in within-run and between-run precision were less than 10% at weighed-in concentrations of 0.545, 1.090 and 2.180 ng/ml. The accuracy relative to the three weighed-in concentrations ranged from 97% to 123% for all methods. One hundred and three plasma samples from 60 patients receiving digoxin were used to evaluate the data compatibility. Digoxin concentrations measured by the three immunoassay systems correlated well with one another. These results suggest that there are few problems when switching between digoxin assay methods, and that IMx and OPUS are more useful than TDx because they do not require sample pretreatment. The digoxin concentrations of the plasma samples from one patient receiving both digoxin and potassium canrenoate were investigated as a case report. The digoxin concentrations measured by TDx and IMx became higher than those measured by OPUS after starting the combination treatment. In another patient suffering from bilirubinaemia, the digoxin concentrations measured by TDx or IMx were higher than those measured by OPUS. These results suggest that OPUS has a higher specificity for measuring the plasma digoxin concentrations compared with TDx or IMx.